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NKD1 targeting PCM1 regulates the therapeutic effects of homoharringtonine on colorectal cancer

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Abstract

Background

Colorectal cancer (CRC) is the most common primary malignancy. Recently, antineoplastic attributes of homoharringtonine (HHT) have attracted lots of attention. This study investigated the molecular target and underlying mechanism of HHT in the CRC process by using a cellular and animal models.

Methods

This study first detected the effects of HHT on the proliferation, cell cycle and apoptosis ability of CRC cells using CCK-8, Edu staining, flow cytometry and Western blotting assay. In vitro recovery experiment and in vivo tumorigenesis experiment were used to detect the targeted interaction between HHT and NKD1. After that, the downstream target and mechanism of action of HHT targeting NKD1 was determined using quantitative proteomics combined with co-immunoprecipitation/immunofluorescence assay.

Results

HHT suppressed CRC cells proliferation by inducing cell cycle arrest and apoptosis in vitro and vivo. HHT inhibited NKD1 expression in a concentration and time dependent manner. NKD1 was overexpressed in CRC and its depletion enhanced the therapeutic sensitivity of HHT on CRC, which indicating that NKD1 plays an important role in the development of CRC as the drug delivery target of HHT. Furthermore, proteomic analysis revealed that PCM1 participated the process of NKD1-regulated cell proliferation and cell cycle. NKD1 interacted with PCM1 and promoted PCM1 degradation through the ubiquitin-proteasome pathway. The overexpression of PCM1 effectively reversed the inhibition of siNKD1 on cell cycle.

Conclusions

The present findings revealed that HHT blocked NKD1 expression to participate in inhibiting cell proliferation and inducing cell apoptosis, ultimately leading to obstruction of CRC development through NKD1/PCM1 dependent mechanism. Our research provide evidence for clinical application of NKD1-targeted therapy in improving HHT sensitivity for CRC treatment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was funded by First-Class Discipline Construction Founded Project of Ningxia Medical University and the School of Clinical Medicine (No. NXYLXK3020071). Ningxia Natural Science Foundation (No. 2021AAC03350). Special Talent Introduction Project of Ningxia Autonomous Region Key R&D Programs (No. 2021BEB04046). The sixth group of Ningxia Autonomous Region Young Scientific and Technological Talent Lifting Project (No. NXKJTJ2021119). Special Project for Discipline Construction of the General Hospital of Ningxia Medical University (No. 2020 − 149). Ningxia high level science and technology innovation leading talent project (Grant No. KJT2019003).

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Authors and Affiliations

  1. Department of Beijing National Biochip Research Center Sub-Center in Ningxia, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China

    Jia Cao, Jia Wang, Rong Ma, Jinhai Tian, Qi Huang, Jingjing Yu & Libin Wang

  2. Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China

    Jia Cao, Jia Wang, Rong Ma, Qi Huang & Jingjing Yu

  3. College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China

    Xiang Tao, Jufen Zhao & Libin Wang

  4. Department of Emergency, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China

    Bin Shi

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  1. Jia Cao
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Contributions

Jia Cao contributed to the experimental work, paper writing and editing, performed the data evaluation and material management. Xiang Tao and Rong Ma were mainly responsible for completing some cell experiments. Jia Wang and Jufen Zhao contributed to the molecular experiments. Bin Shi collected and reviewed clinical data. Jinhai Tian was mainly responsible for biological information analysis. Jingjing Yu and Qi Huang contributed to the data evaluation and data sorting. Libin Wang contributed to the funding acquisition, data evaluation, paper editing and project administration. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Libin Wang.

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Ethics approval

This research project was approved by the Medical Research Ethics Committee of General Hospital of Ningxia Medical University (No: 2020 − 877).

Conflict of interest

The authors have declared that no competing interest exists.

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Jia Cao and Xiang Tao contributed equally to this work.

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Cao, J., Tao, X., Shi, B. et al. NKD1 targeting PCM1 regulates the therapeutic effects of homoharringtonine on colorectal cancer. Mol Biol Rep 50, 6543–6556 (2023). https://doi.org/10.1007/s11033-023-08572-5

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